Discovery, Structure–Activity
Relationship,
and Binding Mode of an Imidazo[1,2‑a]pyridine
Series of Autotaxin Inhibitors
Posted on 2017-07-21 - 00:00
Autotaxin
(ATX) is a secreted enzyme playing a major role in the
production of lysophosphatidic acid (LPA) in blood through hydrolysis
of lysophosphatidyl choline (LPC). The ATX–LPA signaling axis
arouses a high interest in the drug discovery industry as it has been
implicated in several diseases including cancer, fibrotic diseases,
and inflammation, among others. An imidazo[1,2-a]pyridine
series of ATX inhibitors was identified out of a high-throughput screening
(HTS). A cocrystal structure with one of these compounds and ATX revealed
a novel binding mode with occupancy of the hydrophobic pocket and
channel of ATX but no interaction with zinc ions of the catalytic
site. Exploration of the structure–activity relationship led
to compounds displaying high activity in biochemical and plasma assays,
exemplified by compound 40. Compound 40 was
also able to decrease the plasma LPA levels upon oral administration
to rats.
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Joncour, Agnès; Desroy, Nicolas; Housseman, Christopher; Bock, Xavier; Bienvenu, Natacha; Cherel, Laëtitia; et al. (2017). Discovery, Structure–Activity
Relationship,
and Binding Mode of an Imidazo[1,2‑a]pyridine
Series of Autotaxin Inhibitors. ACS Publications. Collection. https://doi.org/10.1021/acs.jmedchem.7b00647
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AUTHORS (34)
AJ
Agnès Joncour
ND
Nicolas Desroy
CH
Christopher Housseman
XB
Xavier Bock
NB
Natacha Bienvenu
LC
Laëtitia Cherel
VL
Virginie Labeguere
CP
Christophe Peixoto
DA
Denis Annoot
LL
Luce Lepissier
JH
Jörg Heiermann
WH
Willem Jan Hengeveld
GP
Gregor Pilzak
AM
Alain Monjardet
EW
Emanuelle Wakselman
VR
Veronique Roncoroni
SL
Sandrine Le Tallec
RG
René Galien
CD
Christelle David
NV
Nele Vandervoort